We examined the association of the onset of dementia with the time course of cognitive performance in tests of episodic memory, executive function, and verbal intelligence from the Baltimore Longitudinal Study of Aging. Using change point analyses to identify the initiation of significant declines in performance before the onset of dementia, we found that declines in performance on tests of episodic memory accelerated 7 years before diagnosis; executive function accelerated 2-3 years before diagnosis; and verbal intelligence declined in close proximity to diagnosis. Identifying the onset of pre-clinical disease may become important as we develop biomarkers for disease onset and as we develop therapies because it is likely to indicate when therapies might be most effective. However, the present study can tell us only the aggregate onset timing. It cannot tell us when the onset is likely for particular individuals. Clearly, further work is required before these studies reach their potential.[unreadable] [unreadable] Alzheimers disease pathology is present in many individuals with no symptoms of dementia or cognitive deficits before death. The implications of this pathology are unknown. It either signifies the early presence of disease that fails to manifest behaviorally in cognitive performance. Or, it represents normal aging and is not disease, per se. If the former, these individuals would have eventually manifested symptoms of dementia had they lived longer. If the latter, our interpretation of Alzheimers pathology may be incomplete. Using data from the Baltimore Longitudinal Study of Aging Autopsy Study, we examined participants who underwent prospective neuropsychological and neurological evaluations before autopsy. These participants and their families agreed to autopsy following death. They were followed with annual home examinations when they were unable to return to the National Institute on Aging. Our main objective was to determine whether cognitive trajectories differed between clinically normal participants with and without Alzheimers disease neuropathology. In addition, we investigated whether clinically impaired individuals showed accelerated rates of cognitive decline compared with clinically normal elderly adults. We found that clinically normal elderly individuals with and without AD neuropathology had similar cognitive trajectories across several cognitive domains. In contrast, individuals with mild cognitive impairment or clinical Alzheimers disease had steeper rates of longitudinal decline in several domains of cognition compared with clinically normal elderly individuals regardless of whether the latter had Alzheimers neuropathology. Moreover, the cognitive differences between impaired and unimpaired groups could be detected years before a diagnosis of dementia. These results suggest that clinically normal individuals with and without Alzheimers neuropathology do not differ in rates of cognitive decline across a number of cognitive domains.[unreadable] [unreadable] The main finding of this prospective study of autopsied BLSA participants is that clinically normal elderly individuals with Alzheimers neuropathology do not differ from those free of Alzheimers neuropathology in rates of change in cognitive performance over time. With the exception of Cued Selective Reminding, neuropsychological tests tapping a number of cognitive domains showed comparable performance trajectories for Normal and Asymptomatic-AD groups. Although the two groups differed significantly on Cued Selective Reminding, a memory test, the Asymptomatic-AD group remained stable, whereas the Normal group showed a decline in performance over time. Our findings extend the observations reported by several groups that substantial Alzheimers neuropathology may be present before cognitive deficits become evident.[unreadable] [unreadable] We also examined the effect of clinically overt stroke on the risk of dementia using clinical data from participants in the Baltimore Longitudinal Study of Aging Autopsy Study. Among participants aged 70 and older who were evaluated yearly for a mean of 10 years, we found that clinical stroke was a risk factor for dementia. However, the majority of participants who became demented after stroke had mild cognitive impairment that did not meet criteria for dementia preceding the initial stroke. In contrast, participants with normal cognition at the time of stroke did not have an increased risk of dementia. Thus, it appears that stroke is a risk factor for the conversion of mild cognitive impairment to frank dementia. These data suggest that preexisting cognitive status is the crucial determinant of post-stroke dementia.[unreadable] [unreadable] The literature on the association of stroke and dementia agrees that cerebral infarcts are a significant risk for clinical dementia. The literature also agrees that Alzheimers pathology and vascular pathology contribute additively, but not interactively, to the clinical manifestation. However, the literature is equivocal about importance of vascular risk factors, asymptomatic infarcts, infarct size, and infarct location as causes of dementia. In a follow-on study, we examined the risk for dementia associated with brain infarcts in participants from the Baltimore Longitudinal Study of Aging Autopsy Study. Brain infarcts were common in this cohort. Both symptomatic and asymptomatic infarcts were associated with increased risk for dementia, but risk factors for stroke (e.g., hypertension) did not increase the risk for dementia in the absence of an infarct. Risk for dementia was associated with the number of infarcts, but not the size or location of hemispheral infarcts. Microscopic infarcts had similar risk for dementia as macroscopic infarcts. Analyses of the effect of infarcts and Alzheimers pathology on dementia indicated that Alzheimers pathology alone accounted for 50% of the dementia in this cohort, and 35% was accounted for by hemispheral infarcts alone or in conjunction with Alzheimers disease.[unreadable] [unreadable] It is common to find substantial numbers of A-beta plaques and neurofibrillary tangles in autopsy brains of older individuals with documented normal cognition, a condition we define as asymptomatic Alzheimers pathology. We examined the morphometric changes of neurons in asymptomatic Alzheimer's disease, a condition characterized by the presence of Alzheimers lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of neurons from the anterior cingulate gyrus and CA1 hippocampal regions in individuals with asymptomatic Alzheimers disease (n=9), Alzheimers dementia (n=8), mild cognitive impairment (n=9), and age-matched controls (n=9). In anterior cingulate gyrus, we observed a significant decrease in the neuronal volume of mild cognitive impairment and Alzheimers disease compared to controls, but no such atrophy in asymptomatic Alzheimers. Moreover, we found a significant increase (p<0.01) in nuclear volume in asymptomatic Alzheimers compared to controls, mild cognitive impairment, and Alzheimers disease brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to A-beta or Tau, or a compensatory mechanism that forestalls the progression of Alzheimers disease and allows the brain to resist the development of dementia. In a follow-up to this study, we recently extended this finding to additional regions and to nucleolar as well as nuclear hypertrophy in cingulate and hippocampal regions.